Cone photoreceptors function under daylight conditions and are essential for color perception and vision with high temporal and spatial resolution. A remarkable feature of cones is their ability to remain functional in bright light which requires powerful adaptation mechanisms of their phototransduction cascade. In rods, light adaptation is mediated by calcium and the mechanisms by which reduction in calcium upon photo-activation modulates phototransduction are well understood. While photo-activation also triggers a decline in calcium in cones, the molecular mechanisms by which this exerts negative feedback on cone phototransduction are not known. The experiments described here will employ physiological studies from available genetically modified mice to investigate the mechanisms of modulation of the cone phototransduction cascade by calcium. Specifically, we will test the hypothesis that regulation of visual pigment phosphorylation by rhodopsin kinase via recoverin is a component of the calcium feedback in mouse cones and modulates their phototransduction in darkness and during light adaptation. We will also test the hypothesis that regulation of cGMP synthesis by guanylyl cyclase via Guanylyl Cyclase Activating Proteins (GCAPs) is a major component of the calcium feedback in mouse cones and modulates their phototransduction in darkness and during light adaptation. Together, these experiments will help us determine the mechanisms that allow cones to adapt to a very wide range of light intensities and remain functional throughout the day, even in bright light. PUBLIC HEALTH RELEVANCE: The experiments outlined in this proposal seek to establish the mechanisms that enable mammalian cones to function in bright light, an essential property for the photoreceptors that mediate daytime vision. These studies will help us understand the role of calcium in regulating mammalian cone function under normal and pathological conditions.